Jan Brandt

Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial

UNLABELLED BACKGROUND Treatment options for patients with ankylosing spondylitis are few. We aimed to assess the effectiveness of infliximab, an antibody to tumour necrosis factor (TNF)-alpha, in treatment of such patients. METHODS In this 12-week placebo-controlled multicentre study, we randomly assigned 35 patients with active ankylosing spondylitis to intravenous infliximab (5 mg/kg) and 35 to placebo at weeks 0, 2, and 6. One patient in the infliximab group was withdrawn from the study. Our primary outcome was regression of disease activity of at least 50%. To assess response, we used validated clinical criteria from the ankylosing spondylitis assessment working group, including disease activity (BASDAI), functional indices (BASFI), metrology (BASMI), and quality of life (short form 36). Analyses were done by intention to treat. FINDINGS 18 (53%) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50% compared with three (9%) of 35 on placebo (difference 44% [95% CI 23-61], p<0.0001). Function and quality of life also improved significantly on infliximab but not on placebo (p<0.0001 and p<0.0001, respectively). Treatment with infliximab was generally well tolerated, but three patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia. INTERPRETATION Our results show that treatment with infliximab is effective in patients with active ankylosing spondylitis. Since there are some potentially serious adverse effects, we recommend that this treatment mainly be used in co-operation with rheumatological centres.

Successful treatment of active ankylosing spondylitis with the anti–tumor necrosis factor α monoclonal antibody infliximab

OBJECTIVE Tumor necrosis factor alpha (TNFalpha) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFalpha monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS). METHODS Eleven patients with AS of short duration (median 5 years, range 0.5-13 years) that had been active for at least 3 months (range 3-72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted > 1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients. RESULTS One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2-6 weeks after the third infusion revealed improvement in 2. Improvement of > or = 50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41-94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6-90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0-28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts. CONCLUSION These data suggest that anti-TNFalpha therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.

Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab

We analyzed the clinical response and the time to relapse after discontinuation of continuous long-term infliximab therapy in patients with ankylosing spondylitis (AS). After 3 years of infliximab therapy, all AS patients (n = 42) discontinued treatment (time point (TP)1) and were visited regularly for 1 year in order to assess the time to relapse (TP2). Relapse was defined as an increase to a value ≥ 4 on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and a physicians global assessment ≥ 4 according to the recommendations of the Assessments in Ankylosing Spondylitis (ASAS) working group. After 52 weeks, 41 of the 42 patients (97.6%) had to be reinfused because of relapse. The mean change in the BASDAI between TP1 and TP2 was 3.6 ± 1.7 and that in the physicians global assessment was 4.4 ± 1.8 (both P < 0.001). The mean time to relapse was 17.5 weeks (± 7.9 weeks, range 7 to 45). Ten patients (24%) showed a relapse within 12 weeks and 38 patients (90.5%), within 36 weeks. After 52 weeks, only one patient had remained in ongoing remission without further treatment with anti-tumor-necrosis factor. Patients who were in partial remission according to the ASAS criteria and those with normal C-reactive protein levels at the time point of withdrawal had longer times to relapse after discontinuation of the treatment. Retreatment with infliximab was safe and resulted in clinical improvement in all patients to a state similar to that before the treatment was stopped. Discontinuation of long-term therapy with infliximab eventually led to relapse of disease activity in all patients but one.

Conventional treatments for ankylosing spondylitis

Management of ankylosing spondylitis (AS) is challenged by the progressive nature of the disease. To date, no intervention is available that alters the underlying mechanism of inflammation in AS. Currently available conventional treatments are palliative at best, and often fail to control symptoms in the long term. Current drug treatment may perhaps induce a spurious state of “disease remission,” which is merely a low level of disease activity. Non-steroidal anti-inflammatory drugs are first line treatment, but over time, the disease often becomes refractory to these agents. Disease modifying antirheumatic drugs are second line treatment and may offer some clinical benefit. However, conclusive evidence of the efficacy of these drugs from large placebo controlled trials is lacking. Additionally, these drugs can cause treatment-limiting adverse effects. Intra-articular corticosteroid injection guided by arthrography, computed tomography, or magnetic resonance imaging is an effective means of reducing inflammatory back pain, but controlled studies are lacking. A controlled study has confirmed moderate but significant efficacy of intravenous bisphosphonate (pamidronate) treatment in patients with AS; further evaluation of bisphosphonate treatment is warranted. Physical therapy and exercise are necessary adjuncts to pharmacotherapy; however, the paucity of controlled data makes it difficult to identify the best way to administer these interventions. Surgical intervention may be required to support severe structural damage. Thus, for patients with AS, the future of successful treatment lies in the development of pharmacological agents capable of both altering the disease course through intervention at sites of disease pathogenesis, and controlling symptoms.

New treatment options in spondyloarthropathies: increasing evidence for significant efficacy of anti–tumor necrosis factor therapy

Tumor necrosis factor-&agr; is a major effector and regulatory cytokine, which seems to have an outstanding position in rheumatic and other inflammatory states. Because TNF-&agr; has been detected in the inflamed gut and sacroiliac joints of patients with chronic inflammatory bowel diseases and spondyloarthritides, like ankylosing spondylitis, there was need for studies of the efficacy of the modern biologic anti-TNF agents infliximab and etanercept in these diseases. Infliximab is approved for the treatment of Crohn disease. In addition, there are now also positive data for infliximab in the treatment of ankylosing spondylitis and for etanercept and infliximab in the treatment of psoriatic arthritis.

Biologic therapies in the spondyloarthritis: new opportunities, new challenges.

Therapeutic options for patients suffering from the more severe forms of spondyloarthritis have been rather limited in the last decades. There is now accumulating evidence that antitumor necrosis factor therapy is highly effective in spondyloarthritis, especially in ankylosing spondylitis and psoriatic arthritis. Based on the data recently published on more than 500 patients with ankylosing spondylitis and psoriatic arthritis, this treatment seems to be even more effective than in rheumatoid arthritis. The antitumor necrosis factor-&agr; agents currently available, infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira), are approved for the treatment of rheumatoid arthritis in the United States and partly in Europe. The situation in spondyloarthritis is different from that of rheumatoid arthritis because there is an unmet medical need, especially in ankylosing spondylitis: no therapies with disease-modifying antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, tumor necrosis factor blockers may even be considered a first-line treatment in a patient with active ankylosing spondylitis and psoriatic arthritis whose condition is not sufficiently controlled with nonsteroidal antiinflammatory drugs in the case of axial disease, and sulfasalazine or methotrexate in the case of peripheral arthritis. For infliximab, a dose of 5 mg/kg was required, and intervals between 6 and 12 weeks were necessary to suppress disease activity constantly—also a major aim for long-term treatment. The standard dosage of etanercept is 2 × 25 mg subcutaneously per week. There are no studies yet on adalimumab (standard rheumatoid arthritis dose, 20–40 mg subcutaneously every 1–2 weeks) in spondyloarthritis. Infliximab was very recently approved for AS in Europe. The efficacy of etanercept was first demonstrated in psoriatic arthritis, and it is now approved for this indication. A double-blind study has also been performed in ankylosing spondylitis, with similarly clear efficacy. There is preliminary evidence that both agents do also work in other spondyloarthritis, such as undifferentiated spondyloarthritis. Ideally, both agents will be approved soon for the short-term treatment of severe, uncontrolled spondyloarthritis. In parallel, studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis may be preventable, but it remains to be shown whether patients benefit from long-term antitumor necrosis factor therapy and whether radiologic progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. These can be largely prevented by appropriate screening. At it stands now, the benefits of antitumor necrosis factor therapy in ankylosing spondylitis seem to outweigh these shortcomings.

Treatment of spondyloarthropathies with antibodies against tumour necrosis factor α: first clinical and laboratory experiences

Drug treatment of patients with spondyloarthropathies (SpA), especially ankylosing spondylitis (AS) has limited capacity.1 Pain but not disease activity can be reduced by non-steroidal anti-inflammatory drugs (NSAIDs), in severe cases very high doses are needed.2 By examination of sacroiliac biopsy specimens we have shown that, in correlation to disease activity assessed by magnetic resonance imaging (MRI), T cells and macrophages3 and tumour necrosis factor α (TNFα) mRNA4 and protein (fig 1) but no bacterial DNA5 is present in these joints that are pathognomonically involved in AS.6 Furthermore, anti-TNFα monoclonal antibodies (mAb) have recently been shown to be efficacious in Crohns disease7—a disease that is strongly linked to AS because more than 60% of AS patients have clinically often silent gut lesions resembling Crohns colitis.8 Furthermore, in another chronic inflammatory rheumatic disease, rheumatoid arthritis (RA), anti-TNF treatment has proved efficacious and even seems to prevent joint damage.9 Figure 1 Immunohistological examination of a sacroiliac biopsy specimen obtained by computed tomography guided biopsy of a 23 year old patient with ankylosing spondylitis, four years disease duration, with inflammatory back pain grade 6 on a visual analogue scale (0–10). The red staining indicates a mononuclear cell positive for TNFα (APAAP staining technique). TNFα is a cytokine that is mainly produced by monocytes and macrophages and to a lesser degree by T cells. There are two specific receptors, a 55 kDa and a 75 kDa present on many cell types. TNFα mediates inflammatory and immunoregulatory activities. Effects on cells such as lymphocyte activation and fibroblast proliferation, on mediators such as other cytokines like interleukin 1(IL1), IL6 and IL8, chemokines, prostaglandins, metalloproteinases, on the vasculature by promoting angiogenesis and on upregulation of adhesion molecules and transendothelial migration of leucocytes are well described. In in vitro and in …

Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis

Objective To establish the predictive validity of the Assessment of SpondyloArthritis international Society (ASAS) spondyloarthritis (SpA) classification criteria. Methods 22 centres (N=909 patients) from the initial 29 ASAS centres (N=975) participated in the ASAS-cohort follow-up study. Patients had either chronic (>3 months) back pain of unknown origin and age of onset below 45 years (N=658) or peripheral arthritis and/or enthesitis and/or dactylitis (N=251). At follow-up, information was obtained at a clinic visit or by telephone. The positive predictive value (PPV) of the baseline classification by the ASAS criteria was calculated using rheumatologists diagnosis at follow-up as external standard. Results In total, 564 patients were assessed at follow-up (345 visits; 219 telephone) with a mean follow-up of 4.4 years (range: 1.9; 6.8) and 70.2% received a SpA diagnosis by the rheumatologist. 335 patients fulfilled the axial SpA (axSpA) or peripheral SpA (pSpA) criteria at baseline and of these, 309 were diagnosed SpA after follow-up (PPV SpA criteria: 92.2%). The PPV of the axSpA and pSpA criteria was 93.3% and 89.5%, respectively. The PPV for the ‘clinical arm only’ was 88.0% and for the ‘clinical arm’±‘imaging arm’ 96.0%, for the ‘imaging arm only’ 86.2% and for the ‘imaging arm’+/-‘clinical arm’ 94.7%. A series of sensitivity analyses yielded similar results (range: 85.1–98.2%). Conclusions The PPV of the axSpA and pSpA criteria to forecast an experts diagnosis of ‘SpA’ after more than 4 years is excellent. The ‘imaging arm’ and ‘clinical arm’ of the axSpA criteria have similar predictive validity and are truly complementary.

Anti-TNF-α agents in the treatment of psoriatic arthritis

Psoriatic arthritis (PsA) is a potentially debilitating disease that may affect small and large peripheral joints, entheses and the axial skeleton. The different clinical manifestations of PsA have been accounted for by various proposals of subdividing the patients into different subgroups. According to the predominant clinical symptoms, most patients can be classified as belonging to the spectrum of spondyloarthritides (SpA) or rheumatoid arthritis (RA). The conventional therapeutic approach comprises non-steroidal anti-inflammatory drugs, systemic and intra-articular corticosteroids, and disease-modifying antirheumatic drugs such as sulfasalazine, methotrexate, ciclosporin and leflunomide. Similar to RA, recent trials in PsA have shown excellent results with the tumour necrosis factor (TNF) blockers etanercept, infliximab and adalimumab, which have positive effects not only on joints, but also on the skin when affected by psoriasis, quality of life, function and slowing of disease progress, as evidenced radiologically. Anti-TNF therapy has been generally safe in clinical trials of PsA. Taken together, there has been definite recent progress in the treatment of PsA, especially for severely affected patients.

The Anti-mutated Citrullinated Vimentin Response Classifies Patients with Rheumatoid Arthritis into Broad and Narrow Responders

Objective. Autoantibodies against citrullinated peptide antigens (ACPA) are routinely determined to diagnose rheumatoid arthritis (RA) and are predictive of a more severe course of the disease. We here set out to address an involvement of ACPA in the pathogenesis of RA and investigated the recognition pattern of antibodies against 2 citrullinated antigens in more detail. Methods. The sera of 77 patients fulfilling the American College of Rheumatology criteria for RA were analyzed for subclass titers of anti-mutated citrullinated vimentin (MCV) and anticyclic citrullinated peptide (CCP) antibodies by combining subclass specific detection antibodies with commercially available CCP and MCV ELISA plates. Cross-reactivities between anti-MCV and anti-CCP antibodies were detected using a sequential ELISA system. Results. IgG1, IgG3, and IgG4 titers among anti-MCV and anti-CCP antibodies correlated significantly. Cross-reactivity of MCV-specific antibodies against CCP could be detected in 8 of 16 patients’ sera; however, cross-binding of MCV-specific IgG4 was weaker compared to total IgG. Conclusion. The inherent capacity of IgG4 to exchange F(ab) arms provides insight into the anti-MCV antibody diversity and suggests a classification of ACPA positive patients into broad and narrow responders.